Delivery devices for nasopharyngeal mucosa targets

ABSTRACT

A system for delivering a therapeutic agent to nasopharyngeal mucosa tissue has a shaft, a porous pad of compliant material coupled to the shaft near the distal end, and a drug reservoir. The porous pad is configured to expand from a contracted configuration to an expanded configuration. The expanded configuration is adapted to engage and conform to the mucosa tissue in a nasal cavity, and the contracted configuration has a size suitable for introduction into the nasal cavity. The drug reservoir holds a therapeutic agent and is at least partially covered by the porous pad. The drug reservoir is configured to release a fixed volume of the therapeutic agent into the porous pad within a period of less than about 120 minutes, and has a wall with a plurality of channels fluidly coupled with the porous pad.

CROSS-REFERENCES TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 14/151,588 (Attorney Docket No. 38077-721.301), filed Jan. 9,2014, which is a continuation of International PCT Application No.PCT/US2012/046258 (Attorney Docket No. 38077-721.601), filed Jul. 11,2012, which is a PCT of, and claims the benefit of U.S. ProvisionalPatent Application No. 61/507,422 (Attorney Docket No. 38077-721.101)filed Jul. 13, 2011; the entire contents of which are incorporatedherein by reference.

This application is related to U.S. patent application Ser. No.11/750,967 (Attorney Docket No. 38077-714.201, formerly 020979-003720US)filed May 18, 2008, the entire contents of which are incorporated hereinby reference. The present application is also related to U.S.Provisional Patent Application No. 61/507,417 (Attorney Docket No.38077-720.101) filed Jul. 13, 2011, the entire contents of which areincorporated herein by reference.

BACKGROUND OF THE INVENTION 1. Field of the Invention

The present disclosure relates generally to medical methods and deliverysystems. More particularly, the present disclosure relates to methodsand systems for delivering therapeutic agents such as toxins ornon-toxins to mucosa targets in a nasopharyngeal space.

Rhinitis is commonly referred to as “stuffy nose,” and results frominflammation and swelling of the mucus membranes lining the nasalcavity. Rhinitis falls into two major categories—allergic andnon-allergic (or vasomotor). Chronic rhinitis can result in chronicinflammation of the nasal passages resulting in sinusitis, an infectionor inflammation of the paranasal sinuses. Rhinitis includes the symptomsof rhinorrhea which is commonly referred to as “runny nose.” Rhinorrheadescribes the effluence of mucus from the lining of the nasal passages,nasopharynx, or paranasal sinuses. Rhinorrhea can be a symptom of anumber of diseases such as the common cold, or sinusitis.

Allergic rhinitis is an immunologic response modulated by immunoglobulinE (IgE) and characterized predominantly by sneezing, rhinorrhea, nasalcongestion, and pruritus of the nose. It may be seasonal (a conditioncommonly referred to as hay fever) or perennial. The seasonal form iscaused by allergens released during tree, grass, or weed pollination,whereas the perennial form is caused by allergies to animal dander, dustmites, or mold spores with or without associated pollinosis. Data alsosuggest that urban air pollutants from automobiles and other sources mayhave an adjunctive effect.

Non-allergic rhinitis may be caused by anatomic pathologies such asblockages, as seen in the case of sinusitis. Symptoms may includesneezing, itching, nasal congestion, and a runny nose. Non-allergicrhinitis is a diagnosis of rhinitis without any IgE mediation, asdocumented by allergen skin testing. Hence, the rhinorrhea, sneezing,pruritus, and congestion do not result from allergy or hypersensitivityand continue to persist, whether continuously or sporadically.Non-allergic rhinitis affects 5-10% of the population. Non-allergicrhinitis has 7 basic subclassifications, including infectious rhinitis,non-allergic rhinitis with eosinophilia syndrome (NARES), occupationalrhinitis, hormonal rhinitis, drug-induced rhinitis, gustatory rhinitis,and vasomotor rhinitis. Patients may or may not present with the samesymptoms seen in allergic rhinitis.

While numerous treatments for rhinitis have been proposed over theyears, no single treatment is optimum for all patients or allconditions. Most commonly, hay fever and other forms of rhinitis aretreated with antihistamines which block the inflammatory response. Whileeffective, many antihistamines are also undesirable because they cancause drowsiness, or they may have a limited duration of effect, andthey can present the patient with an on-going cost associated withcontinuous purchase of the drugs.

Recently, a longer term therapy for rhinitis which relies on the use ofbotulinum toxin (BoNT) for blocking mucus production by mucus-producingcells in the nasal membrane has been proposed. Botulinum toxin and otherneurotoxins are capable of disabling adrenergic cells, includingepithelial or goblet cells which are responsible for the majority ofmucus production in the nasal cavity membrane. It has been published inthe scientific literature that introduction of botulinum toxin into thenasal passages of canines can reduce mucus secretion by a significantamount.

While the use of botulinum toxin appears to hold promise for long termrhinitis treatment, it faces a number of challenges before it issuitable for wide spread use in humans. In particular, botulinum toxinis a neurotoxin which could have significant negative effects on apatient if accidentally released outside of the targeted nasal passages.Inadvertent distribution of the toxin to muscles of the oropharynx,mouth, tongue, or elsewhere could result in serious complications to thepatient. Injection of the toxin helps to overcome some of these issuesby directing the toxin to the target area and injection can performedrelatively quickly. However, injections also have some challenges thatcould be overcome, including the fact that injection of the neurotoxintypically requires a local anesthetic to be used, and the fact that manypatients are uncomfortable when seeing a needle being inserted intotheir nostril. Moreover, the use of a needle to inject a toxin deepwithin the nasal cavity can be very difficult. Topical application oftoxins also may have short comings, particularly in terms of theaccuracy of delivery of the toxin. For example, the use ofbotulinum-soaked gauze pads for delivering the toxin to the nasalcavities, as reported in the scientific literature, have limited abilityto uniformly and selectively deliver the botulinum to the regions havinghigh concentrations of preferred target cells, such as epithelial orgoblet cells in the nasopharynx. Sponges inserted into the nose can bedifficult to place, and are hard and uncomfortable when dry, and lackrigidity when wet. Inadvertent compression of a soaked sponge (e.g.against an obstacle during delivery) can result in the drug beingsqueezed out of the sponge too quickly for adjacent mucosa to absorb thedrug, and often in the wrong location. Loading the sponge with atherapeutic agent can also be difficult and time consuming. Aerosolsystems have also been proposed for use in delivering a therapeuticagent, but again, precise control of toxin delivery can be a challenge,especially given the dispersement under pressure. Drug eluting balloonshave also been suggested for delivery of a therapeutic agent to thesinuses, but require precise positioning.

For these reasons, it would be desirable to provide improved methods andsystems for delivering the correct dose of therapeutic agent in acontrolled manner to a target treatment site. Such improved methods andsystems are preferably used to deliver a toxin, such as botulinum toxinto the nasal membrane of a patient, particularly in a patient sufferingfrom rhinitis or other conditions associated with nasal inflammation andconditions, such as sinus headaches and migraine headaches. Othertherapeutic agents including non-toxins may also be delivered. Suchsystems and methods preferably allow easy delivery without requiringvisualization devices such as endoscopes, and preferably do not requireanesthesia. The devices preferably have a compact initial shape forinsertion and may be easily deployed or activated to expand and fill thedesired area of the nasal cavity. The methods and systems should becapable of providing for selective and repeatable delivery of anappropriate dose of the toxins to a defined target areas within thenasal cavities, including particular paranasal sinuses, the nasopharynx,and in some cases substantially the entire nasal cavity. The systems andmethods should provide for the safe, accurate and effective delivery ofa proper dose of the toxins, and in particular should reduce oreliminate the risk of toxin being delivered to non-targeted tissuesoutside of the nasal cavity. At least some of these objectives will bemet by the inventions described herein below.

2. Description of the Background Art

Patents and publications related to delivery of a toxin to the nasalcavity include U.S. Pat. Nos. 5,766,605 and 6,974,578; and U.S. PatentPublication No. 2005/0281751. Related scientific literature includesSharri et al. (1995) Otolaryngol. Head Neck Surg. 112: 566-571 whichfurther discusses the work disclosed in U.S. Pat. No. 5,766,605. Unal etal. (2002) Acta Otolaryngol 123: 1060-1063 describes the injection ofbotulinum toxin A into the turbinates of patients suffering fromallergic rhinitis. The use of catheters and other devices for theenergy-mediated delivery of botulinum light chain is described incommonly owned co-pending U.S. patent application Ser. No. 11/750,967(Attorney Docket No. 38077-714.201 formerly 020979-003720US), the entirecontents of which are incorporated herein by reference.

BRIEF SUMMARY OF THE INVENTION

Briefly and in general terms, the present invention provides methods andsystems for delivery of a therapeutic agent to the nasal cavity. Thetherapeutic agent may be a toxin or a non-toxin. The present disclosurefocuses on preferred embodiments where the invention provides for thedelivery of toxin to and across the nasal membrane tissue to treatvarious conditions and symptoms associated with nasal inflammation,including, rhinorrhea, rhinitis, sinusitis and hay fever. One of skillin the art will appreciate that this is not intended to be limiting andthat other therapeutic agents such as non-toxins may also be used.

The region where the toxin is introduced may comprise any portion of thenasal cavity, such as a single paranasal sinus or portion thereof, amain nasal passage, two or more paranasal sinuses, or in some cases maycomprise substantially the entire nasal cavity of the patient. Aparticular target region for the toxin may comprise the nasopharynxwhich is at the back of the nasal passage. The nasopharynx comprises acluster of epithelial or goblet cells which are responsible for mucussecretion and which are susceptible to the disabling mechanism of thebotulinum toxin and other neurotoxins.

The therapeutic agent to be delivered may be any agent that helpsalleviate the symptoms of rhinitis. Preferred therapeutic agents includetoxins, and the toxin may comprise any neurotoxin capable of disablingmucus secretion in epithelial or goblet cells and other mucus-producingnasal cells. Preferably, the toxin comprises botulinum toxin, althoughother toxins such as ricin, exotoxin A, diphtheria toxin, cholera toxin,tetanus toxin, other neurotoxins, and active fragments thereof may alsofind use.

In addition to the methods described above, the present inventionfurther provides systems for delivering toxins to epithelial or gobletand other target cells as defined above in a nasal membrane.

In a first aspect of the present invention, a system for delivering atherapeutic agent to nasopharyngeal mucosa tissue comprises a shafthaving a proximal end and a distal end, a porous pad of compliantmaterial, and a drug reservoir. The porous pad is coupled to the shaftnear the distal end, and is configured to expand from a contractedconfiguration to an expanded configuration. The expanded configurationis adapted to engage and conform to the mucosa tissue in a nasal cavity,and the contracted configuration has a size suitable for introductioninto the nasal cavity. The drug reservoir holds a therapeutic agent, andis at least partially covered by the porous pad. The drug reservoir isconfigured to release a fixed volume of the therapeutic agent into theporous pad within a period of less than about 120 minutes. The drugreservoir has a wall with a plurality of channels that are fluidlycoupled with the porous pad.

The elongate central member may comprise an elongate shaft, and theelongate shaft may comprise a central lumen extending therethrough. Theelongate shaft may have a lumen that extends between the proximal anddistal ends, and the lumen may be fluidly coupled to the drug reservoir.Control of fluid pressure applied to the lumen may control the flow ofthe therapeutic agent out of the drug reservoir. A sheath may beslidably disposed over the porous pad. The sheath may constrain theporous pad in the contracted configuration, and removal of the sheathfrom the porous pad may allow expansion thereof into the expandedconfiguration when the therapeutic agent wets the porous pad. The porouspad may expand from the contracted configuration to the expandedconfiguration when wetted by the therapeutic agent. The porous pad mayexert a force against the mucosa tissue when in the expandedconfiguration. The system may further comprise a stiffening elementextending at least partially from the proximal end to the distal end ofthe elongate central member. The stiffening member may provide a desiredrigidity and stiffness to the elongate central member so that theelongate central member may be delivered to a desired location.

The porous pad may comprises a sponge or a foamed polymer. The porouspad may also comprise a plurality of channels extending radially outwardtherefrom. The channels may be configured to direct the therapeuticagent toward an external surface of the porous pad. The porous pad maycomprise a plurality of fingers extending outward therefrom, or a loopedsection, or a plurality of protuberances spaced axially apart from oneanother and separated by a gap therebetween. The porous pad may comprisea plurality of axial elements extending distally of the elongate centralmember. Each axially extending element may have a portion of the porouspad disposed thereover, and each axially extending element may be influid communication with the drug reservoir. The porous pad may comprisea plurality of radial elements extending laterally from the elongatecentral member. Each radial element may have a portion of the porous paddisposed thereover, and each radial element may be in fluidcommunication with the drug reservoir. The porous pad may comprise asheet of porous material wrapped around the elongate central member. Thesheet of porous material may be helically wrapped around the elongatecentral member. The porous pad may comprise a support member disposedtherein. The support member may be configured to provide support to theporous pad in the expanded configuration. The porous pad may comprise aplurality of fibers extending radially outward from the central member.The fibers may be configured to be loaded into a syringe in thecontracted configuration, and the fibers may expand into engagement withthe mucosa tissue when discharged from the syringe and in the expandedconfiguration. The system may further comprise a hydrophobic layer ofmaterial disposed between the drug reservoir and the porous pad. Thehydrophobic layer of material may have a plurality of channels disposedtherein that are configured to direct the therapeutic agent from thedrug reservoir to the porous pad.

The drug reservoir may comprise a plurality of pores that are configuredto allow the therapeutic agent to flow from the drug reservoir towardthe porous pad. The system may further comprise a plurality of valvesfluidly coupled with the plurality of pores. The valves may beconfigured to control flow through the pores. The system may furthercomprise a hydrophilic cover surrounding at least a portion of the drugreservoir. The hydrophilic cover may be configured to facilitatetransport of the therapeutic agent from the drug reservoir toward anexternal surface of the porous pad. The drug reservoir may comprise aplurality of loops extending distally from the elongate central member.The loops may have a central reservoir extending therethrough. At leastsome of the loops may comprise a stiffening member extendingtherethrough. The stiffening member may be configured to maintainpatency of the central reservoirs. The drug reservoir may comprise anexpandable member, and expansion of the expandable member may advancethe porous pad toward the mucosa tissue. Expansion of the expandablemember may also force the therapeutic agent out of the drug reservoir.

In any of the embodiments, the therapeutic agent may comprise atherapeutic agent such as a toxin or other agent including a non-toxinwhich is configured to inhibit mucus secretions. The toxin may bebotulinum toxin.

In another aspect of the present invention, a system for delivering atherapeutic agent to nasopharyngeal mucosa tissue comprises an outersyringe barrel having an elongate flexible sheath extending distallytherefrom, and an inner syringe barrel. The inner syringe barrel isslidably disposed in the outer syringe barrel, and the inner syringebarrel has a plunger slidably disposed therein. The inner syringe barrelcontains the therapeutic agent and has a tissue penetrating needleextending distally therefrom. Actuation of the plunger discharges thetherapeutic agent from the tissue penetrating needle. The tissuepenetrating needle is shielded by the outer syringe barrel or theelongate flexible sheath during insertion through the nasal cavity, anddistal advancement of the inner syringe barrel relative to the outersyringe barrel slidaby advances the tissue penetrating needle throughthe elongate flexible sheath to expose a distal tip of the tissuepenetrating needle. The system may further comprise an indicatormechanism for indicating quantity of the therapeutic agent dischargedfrom the tissue penetrating needle. The indicator mechanism may providetactile, auditory, or visual feedback to an operator of the quantity oftherapeutic agent discharged.

In yet another aspect of the present invention, a patch for delivering atherapeutic agent to nasopharyngeal mucosa tissue comprises a substrate,a porous reservoir holding the therapeutic agent and coupled to thesubstrate, and an adhesive layer coupled to the substrate. The adhesivelayer is configured to adhere the patch to the mucosa tissue, and thetherapeutic agent is released from the porous reservoir into the mucosatissue when the patch is adhesively engaged therewith. The patch may beflexible and configured to conform to the anatomy of the nasal cavity.

In still another aspect of the present invention, a system fordelivering a therapeutic agent to a nasopharyngeal mucosa targetcomprises a therapeutic agent disposed in a reservoir and a spray devicefluidly coupled to the reservoir. The spray device is configured todischarge the therapeutic agent under pressure. The pressure may be highenough so that the therapeutic agent penetrates a mucus blanket disposedover the mucosa tissue. The spray device may be configured to controldroplet size of the therapeutic agent discharged therefrom.

In another aspect of the present invention, a system for delivering atherapeutic agent to a nasopharyngeal mucosa target comprises atherapeutic agent disposed in a reservoir, and an applicator having asoft wicking applicator tip. The soft wicking applicator tip is fluidlycoupled with the reservoir such that the therapeutic agent is wickedfrom the reservoir to the wicking applicator tip without applyingpressure thereto. The system may further comprise a pressure applicationmember. Actuation of the pressure application member compresses thereservoir and applies a pressure thereto, thereby increasing the flow oftherapeutic agent therefrom to the wicking applicator tip. The pressureapplication member may comprises a plunger.

In still another aspect of the present invention, a method fordelivering a therapeutic agent to a nasopharyngeal mucosa tissuecomprises inserting a porous pad in a collapsed configuration into anasal cavity, and with the pad of material inserted in the nasal cavity,wetting the porous pad with a therapeutic agent disposed in a drugreservoir thereby expanding the porous pad into an expandedconfiguration that engages the mucosa tissue. The method also comprisesdelivering the therapeutic agent from the porous pad to the mucosatissue.

The porous pad may be substantially dry during the insertion. A sheathmay remain disposed over the porous pad during the insertion. The sheathconstrains the porous pad in the collapsed configuration. Wetting theporous pad may comprise opening at least one valve fluidly coupled withthe drug reservoir to allow the therapeutic agent to flow therefrom tothe porous pad. Pressure may be applied to the drug reservoir therebypushing the therapeutic agent out of the reservoir. Applying pressuremay comprise inflating an expandable member against the drug reservoir.The constraining sheath may be removed from the porous pad, therebyallowing the porous pad to expand into the expanded configuration. Themethod may further comprise reducing or eliminating the symptomsassociated with rhinitis.

In still another aspect of the present invention, a method fordelivering a therapeutic agent to nasopharyngeal mucosa tissue comprisesadvancing an elongate flexible sheath into a nasal cavity with a tissuepenetrating needle thereon enclosed within the elongate sheath, andslidably advancing the tissue penetrating needle distally relative tothe elongate flexible sheath. The tissue penetrating needle advancesthrough the elongate flexible sheath so that a tissue penetrating tip ofthe tissue penetrating needle is exposed. The method also comprisespiercing the nasopharyngeal mucosa tissue with the piercing needle, anddelivering a therapeutic agent from the tissue penetrating needle to thenasopharyngeal mucosa tissue.

The elongate flexible sheath may be coupled to and extend distally froman outer syringe barrel. Advancing the elongate flexible sheath maycomprise moving the outer syringe barrel toward the nasal cavity. Thetissue penetrating needle may be coupled to and extend distally from aninner syringe barrel. Slidably advancing the tissue penetrating needlemay comprise distally moving the inner syringe barrel relative to outersyringe barrel.

Piercing may comprise distally advancing the inner syringe barrelrelative to the outer syringe barrel such that the inner syringe barrelslides through the outer syringe barrel. Delivering the therapeuticagent may comprise discharging the therapeutic agent from an innersyringe barrel. Delivering the therapeutic agent may comprisecontrolling the quantity of the therapeutic agent delivered bymonitoring a visual, tactile, or auditory indicator mechanism. Themethod may further comprise reducing or eliminating the symptomsassociated with rhinitis.

In another aspect of the present invention, a method for delivering atherapeutic agent to nasopharyngeal mucosa tissue comprises inserting apatch carrying a therapeutic agent into a nasal cavity, and attachingthe patch to the nasopharyngeal mucosa tissue. The method also comprisesdelivering the therapeutic agent from the patch to the nasopharyngealmucosa tissue.

The patch may be flexible and may be in a collapsed configuration duringinsertion. Adhering the patch may comprise expanding the patch from thecollapsed configuration into an expanded configuration so that the patchmay conform to the anatomy of the nasal cavity. Attaching the patch maycomprise adhesively bonding the patch to the nasopharyngeal mucosatissue. The patch may comprise a porous reservoir holding thetherapeutic agent, and delivering the therapeutic agent may comprisedischarging the therapeutic agent from the porous reservoir to an outersurface of the patch. The method may comprise reducing or eliminatingsymptoms associated with rhinitis.

In another aspect of the present invention, a method for delivering atherapeutic agent to nasopharyngeal mucosa tissue comprises providing aspray device having a reservoir that holds a therapeutic agent,pressurizing the reservoir, and spraying the therapeutic agent onto thenasopharyngeal mucosa tissue. Pressurizing may comprise pressurizing thereservoir to a pressure sufficient enough such that when sprayed, thetherapeutic agent penetrates a mucus blanket disposed over the mucosatissue. The method may further comprise controlling droplet size of thesprayed therapeutic agent. The method may further comprise reducing oreliminating symptoms associated with rhinitis.

In yet another aspect of the present invention, a method for deliveringa therapeutic agent to nasopharyngeal mucosa tissue comprises providingan applicator having a reservoir that holds a therapeutic agent, andadvancing a soft wicking tip disposed on a distal portion of theapplicator into a nasal cavity. The method also includes painting thenasopharyngeal mucosa tissue with the soft wicking tip wherein thetherapeutic agent is wicked from the reservoir to the soft wicking tipthereby applying a layer of the therapeutic agent to the nasopharyngealmucosa tissue. The method may further comprise applying pressure to thereservoir thereby increasing flow of the therapeutic agent from thereservoir to the soft wicking tip and onto the nasopharyngeal mucosatissue. The method may reduce or eliminate symptoms associated withrhinitis.

In another aspect of the present invention, a system for delivering atherapeutic agent to nasopharyngeal mucosa tissue comprises an elongateshaft having a proximal end and a distal end, an inner expandable memberand an outer expandable member. The inner expandable member is disposednear the distal end and has a contracted configuration sized forintroduction into the nasal cavity and an expanded volume configurationadapted to engage and conform to the mucosa tissue in a nasal cavity.The outer expandable member is disposed over the inner expandable memberand has a contracted configuration sized for introduction into the nasalcavity and an expanded volume configuration adapted to fill the nasalcavity. The system also has a therapeutic agent carried by the outerexpandable member and that is adapted to inhibit mucus secretions.

The inner expandable member may comprise a balloon. The outer expandablemember may also comprise a balloon or a sponge. The inner or outerexpandable member may comprise a plurality of pores that are configuredto allow the therapeutic agent to pass therethrough. The therapeuticagent may comprise a toxin such as botulinum toxin.

In yet another aspect of the present invention, a method for deliveringa therapeutic agent to nasopharyngeal mucosa tissue comprises providinga delivery system having a first expandable member and a secondexpandable member disposed thereover. The first and second expandablemembers each have a collapsed configuration and an expandedconfiguration. The first expandable member is inserted in the collapsedconfiguration into a nasal cavity and the expanded from the collapsedconfiguration to the expanded configuration thereby filling up the nasalcavity. The second expandable member is expanded from the collapsedconfiguration to the expanded configuration so as to engage the mucosatissue in the nasal cavity. The therapeutic agent is then delivered fromthe expandable member to the mucosa tissue.

Expanding the first or second expandable member may comprise inflating aballoon. Expanding the second expandable member may comprise expanding asponge. The expanded configuration of the first expandable member mayhave a larger volume than the expanded configuration of the secondexpandable member. Delivering the therapeutic agent may comprisedelivering a toxin such as botulinum toxin.

These and other embodiments are described in further detail in thefollowing description related to the appended drawing figures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates basic anatomy of the nasal cavity.

FIGS. 2A-2B illustrate an exemplary delivery device having a coveredporous reservoir.

FIGS. 3A-3E illustrate other exemplary delivery devices of a coveredporous reservoir with cover configurations.

FIG. 4 illustrates still another exemplary embodiment of a deliverydevice with a porous reservoir and an alternative cover configuration.

FIGS. 5A-5F illustrate use of a single sheet of material to form aportion of a drug delivery device.

FIG. 6 illustrates an alternative embodiment of a foam contact element.

FIGS. 7A-7B illustrate an exemplary method of delivering a therapeuticagent to a nasal cavity.

FIGS. 8A-8B illustrate another exemplary method of delivering atherapeutic agent to a nasal cavity.

FIGS. 9A-9B illustrate still another exemplary method of delivering atherapeutic agent to a nasal cavity.

FIG. 10 illustrates an exemplary embodiment of a device for delivering atherapeutic agent to a nasal cavity.

FIG. 11 illustrates an exemplary embodiment of a pressurized drugreservoir.

FIGS. 12A-12B illustrate an exemplary method of delivering a therapeuticagent to the nasal cavity.

FIGS. 13A-13C illustrate a porous balloon for delivery of a therapeuticagent to the nasal cavity.

FIG. 13D illustrates another balloon embodiment for delivery of atherapeutic agent.

FIGS. 14A-14C illustrate an embodiment of a delivery device having atissue penetrating needle.

FIGS. 15A-15B illustrate use of the device in FIGS. 14A-14C to deliver atherapeutic agent to the nasal cavity.

FIGS. 16A-16C illustrate use of a nasal patch to deliver a therapeuticagent to the nasal cavity.

FIG. 17 illustrates a paint on device for delivering a therapeuticagent.

FIG. 18 illustrates cilial transport of a therapeutic agent.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is preferably directed to methods and systems fordelivering one or more therapeutic agents including toxins or non-toxinsto target cells within a patient's nasal cavity. The toxins may beintact toxins, such as botulinum toxin, ricin, exotoxin A, diphtheriatoxin, cholera toxin, tetanus toxin, other neurotoxins, and activefragments thereof. Each of these toxins comprises a heavy chainresponsible for cell binding and a light chain having enzyme activityresponsible for cell toxicity.

Botulinum toxin blocks acetylcholine release from cells, such as theepithelial or goblet cells in the nasal membranes responsible for mucushypersecretion, and can thus be effective in accordance with theprinciples of the present invention. The use of energy to permeablize orporate the cell membranes of the epithelial or goblet cells or othermucus-secreting cells of the nasal lining, may facilitate botulinum andother toxins to be preferentially delivered to the targeted epithelialor goblet and other mucus-producing cells. Additionally,energy-mediation allows use of the active or light chains of thesetoxins (having the heavy chains removed or inactivated) for treatments.Normally, the light chains when separated from the cell-binding heavychains of botulinum and the other toxins are incapable of entering thecells and thus will be free from significant cell toxicity. By usingenergy-mediated protocols the toxin light chains may be locally andspecifically introduced into the target cells located within definedregions of the nasal membrane. Thus, even if the toxin fragments areaccidentally dispersed beyond the desired target regions, the fragmentswill not generally enter cells without the additional application ofcell permeablizing or porating energy. For that reason, toxin deliverymethods are particularly safe when performed with toxin fragments, suchas the light chain of botulinum and other toxins.

While the remaining portion of this disclosure will be presented withspecific reference to the botulinum toxin, one of skill in the art willappreciate that other toxins may also be used, including the activefragment of the toxin in combination with energy-mediated deliveryprotocols such as those disclosed in U.S. Patent Applications previouslyincorporated by reference above.

FIG. 1 illustrates the basic anatomy of the nasal cavity. The entranceto the nasal cavity is via the external naris. The anterior-most portionof the nasal cavity is referred to as the nasal vestibule and isenclosed by cartilage and lined by epithelium. Small hairs in thevestibule help filter dust and other contaminants in the air that isbreathed in. Long, narrow, and curled bone shelves line a portion of thenasal cavity. These bones are referred to as nasal concha or turbinates.An upper or superior turbinate, a middle turbinate, and an inferiorturbinate divide the nasal airway into four channel-like air passageswhich direct inhaled air to flow in a steady, regular pattern around thelargest possible surface of cilia and climate controlling tissue.Various sinus cavities are also disposed within the bones of the faceand skull adjacent the nasal cavity. These sinuses, such as the frontalsinus and the sphenoid sinus are mucosa lined airspaces that producemucus. The nasal cavity communicates with the throat via thenasopharynx.

Foam Covered Reservoir Embodiments

FIGS. 2A-2B illustrate an exemplary embodiment of a delivery devicehaving a porous reservoir with a soft covered tip. The delivery device22 includes an elongate catheter shaft 24 having a lumen 25therethrough. The proximal end of the delivery device 22 includes astandard connector 26 such as a Luer connector for fluidly coupling thedelivery device 22 with a source of the toxin, or other therapeuticagent to be delivered therefrom. In preferred embodiments, the connector26 also has a one-way valve to prevent the therapeutic agent, here atoxin such as botulinum toxin from leaking out of the proximal end ofthe shaft 24. The distal portion of the delivery device 22 includes asoft covered portion, here a resilient foam contact element 30 that isdisposed around the shaft 24. A wire support 28 extends through thelumen 25 of elongate shaft 24 and provides stiffness to the shaft tofacilitate advancement into the nasal cavity, and prevent kinking orunwanted bending. Other support members including wires, plasticmembers, nitinol components, sutures, foam elements, etc. may also becoupled to various portion of the delivery system in order to helpprovide support.

FIG. 2B is a cross-section of the resilient foam contact element 30. Theelongate shaft 24 extends under the foam contact element 30, and supportwire 28 preferably extends through lumen 25 of the elongate shaft 24under foam contact element 30. One or more pores 38 extend laterallythrough the sidewall of shaft 24 so that they are in fluid communicationwith lumen 25 which serves as a reservoir 34 for the toxin ortherapeutic agent to be delivered. The reservoir 34 may also be apressure filled bladder. The reservoir 34 may extend only under the foamcontact element 30, or it may extend proximally beyond the foam contactelement 30 into shaft 24. Foam contact element 30 may be a hydrophilicmaterial to help hold and distribute the therapeutic agent. The foamcontact element 32 also may include channels 36, perforations, or slitswhich help direct the therapeutic agent to flow 40 from the lumen 25which acts as reservoir 34, through the pores 38 in the shaft sidewall,through the foam contact element 30 to a surface of the foam contactelement for delivery to the target tissue which in this embodiment ispreferably nasopharyngeal mucosa tissue. Thus, in this embodiment, asyringe or other device may be coupled to the connector 26 and the lumenmay be filled with a therapeutic agent. Thus the lumen 25 acts as areservoir for the therapeutic agent. The therapeutic agent will beabsorbed by the foam contact element for delivery to the tissue.Additional actuation of the syringe may be used to pressurize thetherapeutic agent within the reservoir to help it flow outward into thefoam contact element. Thus, the foam contact element acts as anabsorbent and porous pad. Additionally, the foam contact element, whichmay be made from any number of polymeric foam materials or woven ornonwoven materials including fabrics or synthetics, is preferablyresilient so that it may have a collapsed low profile configurationsuitable for delivery through the confined space of the nostrils andnasal cavity, and also have an expanded larger profile for maximumtissue contact. The foam contact element may be constrained in the lowprofile collapsed configuration with a sheath, cannula, or otherconstraining element (not illustrated), and it may expand once thesheath or constraining element is removed. In preferred embodiments, thefoam contact element in the collapsed configuration has a cross-sectionless than or equal to a 6 mm diameter cylindrical shaft. Additionally,wetting of the foam contact element with the therapeutic agent mayfurther facilitate expansion thereof

The embodiment of FIGS. 2A-2B has a cylindrical shaped body with atapered nosecone. Any number of other geometries for the foam contactelement are also possible. For example, FIGS. 3A-3E illustrate otherexemplary embodiments of foam contact elements that can be used as aporous pad to deliver a therapeutic agent to the target tissue. Otheraspects of the delivery device may generally take the same form asdevice 22 previously described above.

FIG. 3A illustrates a delivery device having an elongate shaft 24 with afoam contact element 30 a adjacent a distal portion of the elongateshaft 24. The foam contact element 30 a has a plurality of wings 42extending therefrom. The wings 42 may be sized and shaped in order toaccommodate various sizes and anatomies in the nasal cavity. The wings42 may be fabricated from any of the materials previously discussed withreference to device 22 in FIGS. 2A-2B. A porous reservoir 34 a similarto reservoir 34 in FIG. 2B may extend under each wing 42 in order toensure even distribution of therapeutic agent to each wing 42. The wings42 may also be collapsed for delivery, and expanded into engagement withtarget tissue.

FIG. 3B illustrates another exemplary embodiment of a delivery devicethat generally takes the same form as the device in FIG. 3A, with themajor difference being that the foam contact element 30 b on a distalportion of the elongate shaft 24 has a plurality of fingers 34 b whichextend distally from elongate shaft 24. In this embodiment, threefingers 34 b form a pattern similar to a bird footprint. One of skill inthe art will appreciate that the length, thickness, and number offingers may be adjusted to fit the nasal cavity being treated. A porousreservoir 34 b similar to the reservoirs previously described may bedisposed in each finger 34 b of the foam contact element 30 b.

FIG. 3C illustrates yet another exemplary embodiment of a deliverydevice that generally take the same form as previous delivery devicesdiscussed above, with the major difference being that the foam contactelement 30 c includes a looped element 46 extending distally from theelongate shaft 24. A porous reservoir 34 c similar to those describedabove extends through the loop 46 so that the therapeutic agent isevenly distributed along the loop. The loop 46 may be retracted into theshaft 24 for delivery, or a constraining sheath (not shown) may bepassed over the loop to compress it into the collapsed configuration fordelivery into the nasal cavity. Upon reaching a desired target treatmentsite, the sheath may be retracted, or the loop 46 may be advanced fromthe shaft 24 so that the loop is unconstrained and expands into itsfully expanded configuration to engage the tissue. The loop 46 may be afoam, a foam-wrapped structural element, or any of the other materialspreviously described above with reference to device 22 in FIGS. 2A-2B.

FIG. 3D illustrates an exemplary embodiment of a delivery device havingvalves. Other features of the device generally take the same form as theprevious delivery devices described above. Elongate shaft 24 extendsunder the foam contact element 30 d. A lumen 25 d extends through shaft24, and a plurality of ports 38 d pass through a sidewall of the shaft24 such that they are fluidly coupled to lumen 25 d which when filledwith a therapeutic agent such as botulinum toxin serves as a drugreservoir 34 d. Valves 48 cover each port 38 d and they are resilientlybiased to close and rest against ports 38 d thereby fluidly closing theports 38 d. However, when the reservoir is pressurized with atherapeutic agent, the valves 48 open up allowing the therapeutic agentto flow 50 and be discharged from the reservoir into the foam contactelement 30 d.

In still another exemplary embodiment, the foam contact element 30 e maycomprise a plurality of axially spaced apart bumps 52 which form finsalong the elongate shaft 24. In this embodiment, four rows of fins areevenly spaced ninety degrees apart around the circumference of shaft 24.Each row is axially staggered relative to an adjacent row. The number offins, number of rows, axial offset, circumferential offset, as well asother aspects of the fin arrangement may be varied according to theanatomy or other relative design criteria. Other aspects of the deliverydevice in FIG. 3E generally take the same form as those previouslydescribed above.

FIG. 4 illustrates another exemplary embodiment of a delivery deviceused to deliver a therapeutic agent such as a toxin like botulinum toxinto tissue. The delivery device includes an elongate central shaft 62 andhaving a lumen 70 extending therethrough. A plurality of fingers 64extend radially outward from shaft 62. Each finger has a central channelthat is fluidly coupled with lumen 70, and each finger 64 has one ormore ports 68 through a sidewall that allow fluid to egress from thefinger into a foam contact element 66. Thus, a therapeutic agent such asbotulinum toxin may be introduced into lumen 70 and the lumen acts as adrug reservoir. The drug may then be discharged from lumen 70, into thefingers and out ports 68 until the therapeutic agent wets foam contactelement 66. The fingers 64 preferably extend perpendicularly from shaft62, however, the fingers may extend at any desired angle. In thisembodiment, four rows of fingers are distributed around thecircumference of shaft 62, each row spaced ninety degrees apart from oneanother. Additionally, adjacent rows are axially offset from oneanother, or staggered. The distal end of shaft 62 may also include afinger with ports 68 and foam contact element 66. Thus, the deliverydevice in FIG. 4 may appear to be similar to the pattern used for bottlebrushes. One of skill in the art will appreciate that the number of rowsof fingers, axial spacing between adjacent rows, as well ascircumferential spacing of rows of fingers, and other aspects ofgeometry may be modified depending on usage.

FIGS. 5A-5F illustrate how a single sheet of laminated material may beused to form a drug reservoir and foam contact element of a deliverydevice similar to those described above. In FIG. 5A, a single sheet ofmaterial, comprising a laminate of a support structure 82 such as a wireframe or other substrate material laminated to an inner liner 88 ahaving a plurality of ports 88 extending through the liner wall, and afoam material or other porous pad 86 laminated to the liner. Thelaminated sheet of material may then be formed into variousconfigurations to form the drug reservoir portion and tissue engagingportion of a drug delivery device. For example, in FIG. 5A, thelaminated sheet of material may be folded over itself with the edgessealed to form a lumen 84 which holds the therapeutic agent and thusfunctions as a drug reservoir 89. The proximal end of the foldedlaminated sheet may then be coupled to an elongated shaft similar tothose discussed above. Thus, in FIG. 5A, the drug is introduced via alumen in an elongated shaft into lumen 84 where it is stored inreservoir 89. The device may be advanced through a nostril into thenasal cavity, and the drug flows 90 through ports 88 into foam contactelement 86. The drug wets the foam contact element 86, and then the drugis delivered to the nasopharyngeal mucosa tissue.

FIG. 5B illustrates another exemplary embodiment where the laminatedsheet 94 similar to that in FIG. 5A is rolled up on itself like acinnamon roll and coupled to an elongate shaft 92 to form the drugdelivery device. FIG. 5C illustrates the laminated sheet 96 in a flatunrolled configuration. It may include structural support features 98such as ribs, support wires, or other structural elements that help itto form cylindrical rolls such as in FIG. 5D. FIG. 5E illustratesanother possible configuration that may be formed by rolling thelaminated sheet 96. It includes lower profile proximal and distal ends106 which may be attached to an elongate shaft (not illustrated), aswell as proximal and distal enlarged profile collars and a smallermiddle profile region 110. Thus different portions of the length of thedevice can expand to different diameters based on the surroundinganatomy. This configuration may be useful for accommodating and treatingvarious anatomical areas of the nasal cavity.

FIG. 5F illustrates still another exemplary embodiment of how thelaminated sheet may be formed into a drug delivery device. An elongateshaft or push wire 110 may be used to wrap the laminated sheet 112around the shaft to form a helix or corkscrew pattern. Rotation and/orlinear advancement of the push wire relative to the laminated sheet 112may expand or contract the helix, thereby increasing or decreasing itsprofile. This may be advantageous since it allows the device to bedelivered into the nasal cavity in a low profile configuration, and thenit may be easily expanded to engage the nasopharyngeal mucosa tissue.

FIG. 6 illustrates an alternative embodiment of a foam contact elementor porous pad material that may be used with any of the foam contactelement embodiments described herein. The foam contact element 212 maybe coupled to an elongate shaft as previously described above, or it maybe coupled to other delivery instruments, or used alone. The foamcontact element 212 includes an outer foam layer 202 that surrounds theporous reservoir 208 having a central lumen 214 for holding atherapeutic agent, and pores 216 that allow the therapeutic agent to bereleased therefrom. A layer of hydrophobic foam 206 is disposed betweenthe outer foam layer 202 and the porous reservoir 208. Channels 204 aredisposed in the hydrophobic foam layer 206 and they help direct thetherapeutic agent to the outer foam layer 202. This configurationprovides a large outer surface area for contact with tissue fordelivering the therapeutic agent, while minimizing the volume oftherapeutic agent that is absorbed into the foam due to the hydrophobiclayer.

FIGS. 7A-7B illustrate an exemplary method of delivering a therapeuticagent to the nasal cavity with a foam contact element. The deliverydevice 230 includes an elongate shaft 240 having a foam contact element234 similar to those described above, adjacent a distal portion of theelongate shaft 240. Disposed under the foam contact element 240 lies aporous reservoir 236 similar to those previously described above. Aconnector 238 coupled to the proximal end of the elongate shaft 240allows a syringe or other device to be fluidly coupled to the elongateshaft and the porous reservoir. An optional sheath 232 may be slidablydisposed over the foam contact element 234 to constrain the foam contactelement into a collapsed configuration that facilitates insertion intothe nasal cavity via a nostril. In FIG. 7B, the delivery device 230 hasbeen advanced into the nasal cavity via a nostril, and sheath 232 hasbeen proximally retracted, thereby allowing the foam contact element toexpand into engagement with nasopharyngeal mucosa tissue. The shape ofthe foam contact element may be varied as discussed above in order toengage specific regions of the nasal cavity. Possible targets includeany of the turbinates as well as the nasal septum, uncinate process,inferior, superior, and lateral extents of the nasopharynx. Thetherapeutic agent, such as botulinum toxin may then be released from thereservoir 236 into the foam contact element 234 and delivered to thetissue. The reservoir may be pre-filled, or a syringe or other devicemay also be coupled to connector 238 to deliver the therapeutic agent tothe reservoir and/or to pressurize the reservoir to facilitate itsdelivery. Wetting of the foam contact element may further result inexpansion of the foam contact element so that it contacts an even largersurface area. The size of the foam contact element may be selecteddepending on the size of the nasal cavity, or the size of the targetarea to treat. In alternative embodiments, multiple delivery devices maybe used to treat a larger area.

The delivery device in FIGS. 7A-7B may be used to treat symptomsassociated with rhinitis. A toxin may be used such as botulinum toxinthat reduces or inhibits mucus production. In an exemplary embodiment,50 U of botulinum toxin A may be hydrated with saline per manufacturer'srecommendations to a concentration of 25 U/ml. Each side of the nose maythen be treated with 1 ml of the therapeutic agent, resulting indelivery of 25 U to the tissue. Dosage may vary, and can be as little as10 U or as large as 200 U. Concentration can vary and may be as great as100 U/ml. In preferred embodiments the delivery device is configured todeliver the full dosage of the therapeutic agent to the tissue within 30minutes, however depending on concentration of the substance, it may bepreferable to deliver more slowly (e.g. over 60 minutes), or morerapidly (e.g. in one to two minutes). Delivery may also occur over atime period somewhere in between these slower and faster time periods.Also, in this as well as other embodiments, the therapeutic agent may bechemically modified to help with absorption through the skin, such as byforming salts of the drug having increased solubility, or by formingesters of the drug that help increase permeability of the mucusmembranes. The use of surfactants may also help modify mucosapermeability. Drugs may also be modified to have increased hydrogenbonding thereby allowing increased mucoadhesiveness to prevent thetherapeutic agent from migrating to undesirable areas. Othermodifications to the therapeutic agent include the use of bioadhesivepolymers such as polyacrylic acid to form a gel-like layer that enhancescontact between the drug and the tissue, resulting in increasedresidence time of the agent. Microspheres, nanoparticles, and liposomesmay also be used to help with mucoadhesiveness.

FIGS. 8A-8B illustrate another exemplary embodiment of delivering atherapeutic agent to the nasal cavity. The delivery device includes aplurality of flexible shafts 254, each having a foam contact element 256disposed on a distal portion of the flexible shaft 254. A porousreservoir (not illustrated) similar to those previously described isdisposed under the foam contact element. An outer sheath 252 is slidablydisposed over the plurality of shafts 254, and the sheath 252 maypartially cover the shafts 254 or entirely cover the shafts 254 and foamcontact elements 256. Thus sheath 252 helps constrain the shafts 254into a lower profile for ease of insertion into the nasal cavity. InFIG. 8B, the delivery device has been advanced into the nasal cavity viaa nostril. The sheath 252 has been retracted relative to the pluralityof flexible shafts 254 allowing the foam contact elements 256 to fan outand contact a larger area of tissue. The therapeutic agent may then bedischarged from the porous reservoir into to the foam and to the tissue,as described previously. Use of multiple flexible shafts and contactelements allow the device to reach smaller, harder to reach areas withinthe nasal cavity, as well as to more easily navigate around obstructionsor through narrow gaps. A delivery device may be used in each side ofthe nose, and multiple delivery devices may be used on a single side.

FIGS. 9A-9B illustrate still another exemplary embodiment of a methodfor delivering a therapeutic agent to the nasal cavity. A porousreservoir (not illustrated, but similar to that previously describedabove) may include a small diameter flexible tube covered with foam oranother expandable and absorbable pad of material. Pores in thereservoir allow a therapeutic agent to be released therefrom into thefoam cover for delivery to the tissue. The foam covered flexible tube280 may be loaded into a syringe 276 for advancement through a nostrilinto the nasal cavity as seen in FIG. 9A. Once the syringe is advancedinto the nasal cavity, the syringe plunger may be actuated and the foamcovered flexible tube 280 is pushed out of the syringe into the nasalcavity as seen in FIG. 9B. Once unconstrained by the syringe, the foamexpands to fill the nasal cavity. A string 278 is coupled to the foamcovered flexible tube, and a free end of the string 278 remains outsideof the nostril. The free end of the string may be pulled in order toremove the foam covered flexible tube. Multiple foam covered tubes maybe inserted into the nasal cavity in order to deliver the therapeuticagent to a larger surface area.

Additional Delivery Device Embodiments

In addition to the embodiments previously described, other exemplaryembodiments are possible. For example, the drug delivery device mayinclude looped elements for delivering the therapeutic agent, apressurized drug reservoir, porous balloons, retractable needles,patches, and paint brush-like embodiments.

FIG. 10 illustrates a delivery device having a plurality of loopeddistal elements 302 coupled to shaft 304. A connector 306 such as a Luerconnector allows a syringe or other device to be fluidly coupled to thedevice to pre-fill the device with the therapeutic agent, or to fill anddeliver the drug during use. A lumen in each loop forms a drug reservoirsimilar to those previously described above. Each loop may have a foamcontact element disposed thereover, or as illustrated, the loops may befoamless. Each loop has a plurality of pores (not illustrated) to allowthe therapeutic agent to be released therefrom. An optional stiffeningmember (not illustrated) such as a wire may be disposed in each loop inorder to help maintain shape and patency of the loop. In alternativeembodiments, the drug reservoir may include an inflatable inner chamberthat can help push the outer surface of the loops against the targettissue, and that will help push the therapeutic agent out of thereservoir. FIG. 11 shows a cross-section of a porous drug reservoir 310with an inflatable inner chamber 312 for facilitating release of thetherapeutic agent 314 through the pores of the reservoir. In addition toloops, the delivery device may have a single porous balloon, an array ofballoon fingers, or corkscrew-like elements for delivering drug to thetarget tissue.

FIGS. 12A-12B illustrate an exemplary method of advancing a drugdelivery device having looped elements into the nasal cavity. The drugdelivery device in FIGS. 12A-12B only has a single looped element, butone of skill in the art will appreciate that it may also have multiplelooped elements, similar to the embodiment in FIG. 10. The loop element344 having the porous drug reservoir is retracted into and constrainedby sheath 342 for minimum profile that can be advanced into the nasalcavity via a nostril. Once the device has been introduced into the nasalcavity, the sheath may be retracted (or the loop may be advanced) sothat the loop becomes unconstrained and it expands into its full shapeas seen in FIG. 12B. The therapeutic agent may then be delivered fromthe loop into the target tissue. Once the drug has been delivered, theloop may be resheathed, and the device removed from the patient's nose.

FIGS. 13A-13C illustrate use of a porous balloon to deliver atherapeutic agent to the nasal cavity. A catheter 372 includes anelongate flexible shaft 374 having a porous balloon 376 disposed at thedistal end of the shaft 374. The balloon 376 includes a plurality ofmicropores 382 in the balloon wall which allow a therapeutic agent to bedelivered therefrom when the balloon is pressurized. An optional foamcontact element (not illustrated) similar to those previously disclosedabove may be disposed over the porous balloon 376. A connector 378, suchas a Luer connector is coupled to a proximal end of the elongate shaft374 in order to allow a syringe or other component to be fluidly coupledto the catheter 372. In FIG. 13B, the catheter 372 is advanced towardthe patient's nasal cavity, and the distal tip is inserted into thenostril. An optional valve member 380 may be coupled to connector 378 toprevent backflow of the therapeutic agent. In FIG. 13C, the balloon 376is advanced into a desired portion of the nasal cavity, and a syringe orother reservoir device (not illustrated) is coupled to valve 380, andthe therapeutic agent is then transferred from the syringe or reservoirto the porous balloon 376. As the balloon inflates, the therapeuticagent passes through the micropores 382 in the balloon wall, and thetherapeutic agent is then delivered to the desired target tissue. In oneembodiment, the volume of the balloon is about 0.3 ml, and it is filledmultiple times during placement and use in order to deliver 1 ml of drugsolution (such as a toxin like botulinum toxin) to one side, or bothsides of the nose. Placement of the balloon may be adjusted betweenfills so that the drug is delivered to different areas of the anatomy.Also, in some embodiments, multiple balloons may be inserted into thenasal cavity for simultaneous delivery of a larger quantity of drug to alarger surface area. A final filling of the balloon with water or asaline solution may be used to flush the remaining drug solution out ofthe balloon, and the device may be removed from the patient's nose.

In an alternative embodiment as seen in FIG. 13D, the delivery system382 includes an elongate shaft 384 having inner balloon 386 and an outerballoon 388 or outer spongy layer 388 disposed near the distal portionof the elongate shaft 384. The outer balloon 388 may be disposed overthe inner balloon 386 or the spongy outer layer 388 may be disposed ontop of the inner balloon 386. In this embodiment, the inner balloon 386does not act as the drug reservoir and is not inflated for the purposeof pushing drug out of the outer balloon or spongy layer. Instead, thespace 387 of the inner balloon 386 is inflated with a fluid such as agas (e.g. air or nitrogen) or saline in order to reduce the remainingvolume of the nasal cavity. Thus, the small remaining volume of thenasal cavity can easily be filled with the inflated outer balloon orspongy layer 388. Therefore the expanded volume of the inner balloon ispreferably greater than the expanded volume of the outer balloon orspongy layer. Because the volume of the nasal cavity has been reduced,the therapeutic agent may be delivered in a higher concentration andlower volume and it will be more precisely delivered to a smallervolume. Using a higher concentration achieves a better therapeuticeffect with a smaller and less dangerous amount of the drug required.The therapeutic agent may be a toxin such as those described in thisspecification or it may be other drugs including non-toxins. Thetherapeutic agent may be delivered via a lumen in shaft 384 to the space389 between the inner and outer balloons and the outer balloon may beporous to allow the drug to be delivered to the tissue, or the drug maybe delivered via a lumen in the shaft 384 to exit ports (notillustrated) on the shaft 384. In other embodiments, the drug may beheld in the spongy layer 388 and delivered to the tissue upon contactthereagainst.

FIGS. 14A-14C illustrate an exemplary embodiment of a drug deliverydevice having a tissue penetrating needle that may be used to deliver atherapeutic agent to nasal cavity. The delivery device includes an outersyringe barrel 404 and an inner syringe barrel 408. In preferredembodiments, the inner syringe barrel is a 3 ml syringe holding a 1 mlvolume of therapeutic agent, and the outer syringe barrel is a 5 mlsyringe, although this is not intended to be limiting. An elongateflexible sleeve 402 is coupled to the distal end of the outer syringebarrel 404, and a tissue penetrating needle 406 is coupled to the distalend of the inner syringe barrel 408. The inner syringe barrel 408 isslidably disposed in the outer syringe barrel 404. The inner syringebarrel serves as a drug reservoir 412 for holding a therapeutic agent.Actuation of plunger 410 by distal advancement forces the therapeuticagent out of the reservoir 412 and through needle 406. In preferredembodiments, the inner syringe barrel 408 is disposed in a retractedposition relative to the outer syringe barrel 404 such that needle 406remains in outer syringe barrel 404, unexposed, as illustrated in FIG.14A. Distal advancement of the inner syringe barrel relative to theouter syringe barrel advances the needle distally through sleeve 402until the distal tissue piercing tip of the needle 406 is exposed, asseen in FIG. 14B. An optional spring 414 may be disposed between adistal end of the inner syringe barrel and a distal portion of the outersyringe barrel. This spring 414 is biased to retract the inner syringebarrel away from the outer syringe barrel, thus the tissue piercingneedle will be biased to remain unexposed in the outer syringe barrel.Once the needle is exposed, the plunger 410 may be distally advanced toforce the therapeutic agent out of the reservoir 412 and out the needle406 into the target tissue.

The device in FIGS. 14A-14C may be used to inject a therapeutic agentsuch as a toxin like botulinum toxin into specific regions of tissuesuch as the turbinates. One injection, or multiple injections may beused. Also, because the needle is covered during initial delivery, thismay help reduce patient anxiety associated with seeing a needle. Also,the sleeve is flexible, and therefore can navigate the nasal anatomyeasier than a more rigid needle. And once the device has been positionedin a desired area of the nasal cavity, the sleeve will act as a guide tohelp the needle smoothly advance through the anatomy to the target. Thismay help reduce patient discomfort and also reduce trauma to the tissue.Also, the amount of needle that is exposed from the sleeve may becontrolled or fixed, thereby controlling the penetration depth whichhelps to prevent overly deep delivery of the therapeutic agent. In someembodiments, an indicator mechanism such as tactile, visual, or auditorymechanisms allow the operator to know when the needle is exposed and howfar it is exposed, and how much drug is delivered. An anesthetic such asLidocaine may also be used to help alleviate patient discomfort. TheLidocaine may be injected separately, or it may be mixed with somecompatible therapeutic agents and injected simultaneously.

FIGS. 15A-15B illustrate exemplary usage of the device in FIGS. 14A-14C.The sleeve 402 is advanced through a nostril into the nasal cavity asseen in FIG. 15A. Advancement of the sleeve is performed while theneedle is retracted into the outer syringe barrel 404. Once the sleevehas been delivered to the target treatment site, the needle 406 isadvanced distally so that it is exposed from the sleeve 402 asillustrated in FIG. 15B. The needle may then be advanced into the tissueand the therapeutic agent delivered therefrom.

FIGS. 16A-16C illustrate the use of a patch to delivery a therapeuticagent to a nasal cavity. The patch 422 may be similar to transdermaldrug delivery patches, and it may include a porous reservoir for holdingand delivering the therapeutic agent 428, and that is joined to aflexible adhesive structure for temporary attachment to the targettissue, such as a nasal turbinate 420. The adhesive areas 424 of thepatch 422 may be arranged to ensure that the patch will stick to thetissue (e.g. mucosa tissue) with or without requiring removal of mucosaprior to application of the patch. Additionally, the adhesive areas 424may be arranged in order to work in concert with the cilial transportmechanism of the underlying mucosa, as indicated by arrow 426. Cilialtransport will be temporarily interrupted in the adhesive locations yetcontinue to function in other areas. This can act to slow the cilialtransport of the drug solution and increase its residence time, or steerthe drug solution away to affect a broader area. The patch 430 may beflexible such that it can be folded and the adhesive side 432 affixed tothe anterior surface of a turbinate 420 as seen in FIG. 16B, or thepatch 430 may be folded in the opposite direction to be placed in themeatus between a turbinate 420 and the nasal septum or another turbinateas seen in FIG. 16C.

Therapeutic agents such as toxins like botulinum toxin may also bespayed on or painted on to a target tissue. Spray applicators may usepressurized gas to spray the drug onto the tissue. Droplet size,viscosity may be controlled, and a broad area may be easily treated withthe therapeutic agent. High pressure spraying may also be used to helpensure that the therapeutic agent penetrates the mucus blanket coveringthe mucosa. In other embodiments, lower pressure may be used to spray amore viscous solution of the therapeutic agent onto the target tissue inorder to increase its residence time for greater drug penetration intothe tissue. While spray methods are promising, in certain situations,the sprays can be hard to control which is undesirable when delivering atoxin. Additional controls may be implemented to help ensure properdelivery of the toxin. For example, delivery may be coordinated with thepatient's breathing such that drug delivery only occurs when the patientexhales. Exhalation produces a strong airflow out of the lungs andcloses the soft palate to seal the nasal cavity from the mouth andinferior pharynx. This prevents toxins from entering the lungs.Additionally, multiple smaller doses may be administered in order tolimit the danger of one large does. Also, viscosity and droplet size maybe controlled to increase residence time and help prevent aspirationinto unwanted areas.

Paint applicators may also be used to deliver a therapeutic agent. Theyallow control over drug application, and also allow broad coverage. FIG.17 illustrates an exemplary embodiment of a paint on applicator. Theapplicator is similar to a felt tipped pen. It includes a drug reservoir452 and a wicking tip 454. Actuation of pressure mechanism 456 movesplunger 458 thereby forcing drug out of the reservoir. The wicking tip454 may be used to paint on the therapeutic agent to a desired targettissue. For example, in FIG. 18, three regions 462 are initially paintedon the turbinate 460 using the device of FIG. 17. Cilial transport 464causes the drug to flow thereby further spreading the drug in the nasalcavity.

While the above is a complete description of the preferred embodimentsof the invention, various alternatives, modifications, and equivalentsmay be used. Therefore, the above description should not be taken aslimiting the scope of the invention which is defined by the appendedclaims.

What is claimed is:
 1. A system for delivering a therapeutic agent tonasopharyngeal mucosa tissue, said system comprising: a shaft having aproximal end and a distal end; a porous pad of compliant materialcoupled to the shaft near the distal end, wherein the porous pad isconfigured to expand from a contracted configuration to an expandedconfiguration, the expanded configuration being adapted to engage andconform to the mucosa tissue in a nasal cavity, and the contractedconfiguration having a size suitable for introduction into the nasalcavity; and a drug reservoir holding a therapeutic agent, the drugreservoir being at least partially covered by the porous pad, the drugreservoir having a wall with a plurality of channels fluidly coupledwith the porous pad.
 2. The system of claim 1, wherein the drugreservoir is configured to release a fixed volume of the therapeuticagent into the porous pad within a period of less than about 120minutes.
 3. The system of claim 1, wherein the elongate central membercomprises an elongate shaft.
 4. The system of claim 3, wherein theelongate shaft comprises a central lumen extending therethrough.
 5. Thesystem of claim 3, wherein the elongate shaft has a lumen extendingbetween the proximal and distal ends, the lumen fluidly coupled to thedrug reservoir.
 6. The system of claim 5, wherein control of fluidpressure applied to the lumen controls the flow of the therapeutic agentout of the drug reservoir.
 7. The system of claim 1, further comprisinga sheath slidably disposed over the porous pad, the sheath constrainingthe porous pad in the contracted configuration, and wherein removal ofthe sheath from the porous pad allows expansion thereof into theexpanded configuration when the therapeutic agent wets the porous pad.8. The system of claim 1, wherein the porous pad expands from thecontracted configuration to the expanded configuration when wetted bythe therapeutic agent.
 9. The system of claim 7, wherein the porous padin the expanded configuration exerts a force against the mucosa tissue.10. The system of claim 1, further comprising a stiffening elementextending at least partially from the proximal end to the distal end ofthe elongate central member, the stiffening element providing a desiredrigidity and stiffness to the elongate central member so that theelongate central member may be delivered to a desired location.
 11. Thesystem of claim 1, wherein the porous pad comprises a sponge.
 12. Thesystem of claim 1, wherein the porous pad comprises a foamed polymer.13. The system of claim 1, wherein the porous pad comprises a pluralityof channels extending radially outward therefrom, the channelsconfigured to direct the therapeutic agent toward an external surface ofthe porous pad.
 14. The system of claim 1, wherein the porous padcomprises a plurality of fingers extending outward therefrom.
 15. Thesystem of claim 1, wherein the porous pad comprises a looped section.16. The system of claim 1, wherein the porous pad comprises a pluralityof protuberances spaced axially apart from one another and separated bya gap therebetween.
 17. The system of claim 1, wherein the porous padcomprises a plurality of axial elements extending distally of theelongate central member, each axially extending element having a portionof the porous pad disposed thereover, and each axially extending elementin fluid communication with the drug reservoir.
 18. The system of claim1, wherein the porous pad comprises a plurality of radial elementsextending laterally from the elongate central member, each radialelement having a portion of the porous pad disposed thereover, and eachradial element in fluid communication with the drug reservoir.
 19. Thesystem of claim 1, wherein the porous pad comprises a sheet of porousmaterial wrapped around the elongate central member.
 20. The system ofclaim 19, wherein the sheet of porous material is helically wrappedaround the elongate central member.
 21. The system of claim 1, whereinthe porous pad comprises a support member disposed therein, the supportmember configured to provide support to the porous pad in the expandedconfiguration.
 22. The system of claim 1, wherein the porous padcomprises a plurality of fibers extending radially outward from thecentral member, the fibers configured to be loaded into a syringe in thecontracted configuration, and wherein the fibers expand into engagementwith the mucosa tissue when discharged from the syringe and in theexpanded configuration.
 23. The system of claim 1, further comprising ahydrophobic layer of material disposed between the drug reservoir andthe porous pad, the hydrophobic layer of materials having a plurality ofchannels disposed therein, the channels configured to direct thetherapeutic agent from the drug reservoir to the porous pad.
 24. Thesystem of claim 1, wherein the drug reservoir comprises a plurality ofpores, the pores configured to allow the therapeutic agent to flow fromthe drug reservoir toward the porous pad.
 25. The system of claim 24,further comprising a plurality of valves fluidly coupled with theplurality of pores, the valves configured to control flow through thepores.
 26. The system of claim 1, further comprising a hydrophilic coversurrounding at least a portion of the drug reservoir, the hydrophiliccover configured to facilitate transport of the therapeutic agent fromthe drug reservoir toward an external surface of the porous pad.
 27. Thesystem of claim 1, wherein the drug reservoir comprises a plurality ofloops extending distally from the elongate central member, the loopshaving a central reservoir extending therethrough.
 28. The system ofclaim 27, wherein at least some of the loops comprise a stiffeningmember extending therethrough, the stiffening member configured tomaintain patency of the central reservoirs.
 29. The system of claim 1,wherein the drug reservoir comprises an expandable member, and whereinexpansion of the expandable member advances the porous pad toward themucosa tissue.
 30. The system of claim 1, wherein the drug reservoircomprises an expandable member, and wherein expansion of the expandablemember forces the therapeutic agent out of the drug reservoir.
 31. Thesystem of claim 1, wherein the therapeutic agent comprises a toxinconfigured to inhibit mucus secretions.
 32. The system of claim 31,wherein the toxin comprises botulinum toxin.